The most common type of adult glioma (a primary malignant brain tumor), glioblastoma, has a five-year survival probability of only 3%. It is therefore important to understand the causes of this tumor with the ultimate goal of improving both prevention and treatment. Ten epidemiologic studies indicate that self-reported allergies appear to reduce glioma risk. Schwartzbaum et al. find that polymorphisms of the IL (interleukin)-13 and IL-4Ralpha precursor genes that increase susceptibility to allergies, decrease glioblastoma risk. In rats, IL-4 and IL-13 cytokines control brain inflammation by inducing regulatory T cell production by astrocytes (brain cells) and by causing the death of microglia (major inflammatory cells of the central nervous system). Much glioma research focuses on treatment and is thus based on fully developed tumors;the study of genetic variants allows insight into early glioma development and may provide clues for prevention or screening. To further understand the relationship between allergies and glioma, our first Specific Aim (1a) is to determine whether allergy susceptibility, regulatory T cell pathway, or other immune function genetic variants are associated with glioma. We identified genes associated with both allergies or regulatory T cells and glioma in the previous literature. Prior evidence for an association between 25 of these genes and glioma is strong enough to justify identification of non-synonymous coding and tag single nucleotide polymorphisms (SNPs) in DNA from 1,173 glioma cases and 2,486 controls. In Specific Aim 1b, we will compare glioma-control distributions of the 9,178 SNPs on the Affymetrix Human Immune and Inflammation Panel using 1,173 glioma cases and 1,173 controls. Our second Specific Aim is to find out whether the association between allergy or immune system polymorphisms is further enhanced by allergic symptoms or reduced by allergy treatments. This aim incorporates the environment, as represented by allergic symptoms and treatment, and may therefore be relevant to glioma prevention. Although IL-4Ralpha allergy susceptibility variants reduce glioma risk, paradoxically, these same variants are also related to reduced glioma survival time, perhaps because of the anti-tumor immunity inhibiting properties of IL-4Ralpha associated cytokines. For our third Specific Aim, we will use survival and treatment data from 943 glioma cases to identify the effects immune function SNPs on glioma survival time. Overall, our proposed study is based on interviews with and DNA samples from 1,173 glioma participants and 2,486 population-based controls. This would make our study among the largest to be conducted. Data will be analyzed using logistic and Cox Proportional Hazards Regression, random forests, Bayesian Networks, and software to identify immune-related pathways to Public Health. The public health relevance of the attached application is two-fold. First, it will allow understanding of the role of the immune system in glioma etiology. Although this tumor is rare, it accounts for more years of life lost than any other tumor. Second, it will determine whether treatment for allergies blocks their natural glioma- preventing properties. This second point has application to the large number of people who use medication to treat their allergies.